The present invention relates to a new pharmaceutical preparation containing cyclosporin(s) for oral application, a process for producing this pharmaceutical preparation, as well as its application for oral administration.
Cyclosporin(s) are cyclic oligopeptides from lower fungi, which were discovered by scientists at Sandoz AG, Basel. Cyclosporin A or Cyclosporin G, in particular, are used as immunosuppressant agents, specifically following organ transplant surgery. The cyclosporin ,derivative "SDZ IMM 125", a hydroxy ethyl derivative of D-serine-8-cyclosporin, is also preferred. The application in the case of other diseases, e.g. , diabetes and psoriasis as well as numerous autoimmune disorders (e.g., rheumatoid arthritis, endogenous uveitis, etc.) has also been described.
Cyclosporin A is obtained as a white amorphous powder from fungi by means of column chromatography over silica gel; it crystallizes from acetone in the form of white needles having a melting point of 148.degree. to 151.degree. C. In addition to cyclosporin A, numerous other cyclosporins are known, ranging from cyclosporin A to cyclosporin Z (cf. Roempp's Chemie Lexikon, 9th edition, pages 841 to 843). Semi-synthetic derivatives of cyclosporin are equally known and may be used in accordance with the invention. These are substances which are very similar to each other from a chemical point of view and which consist of cyclic polypeptides of 11, partially methylated, amino acids. Cyciosporins are soluble in alcohol, ether, acetone and chlorinated hydrocarbons and natural oils (triglycefides of fatty acids).
Cyclosporin A is commercially available for oral application in the form of capsules as well as a solution for administration per os. In both forms of administration the cyclosporin is dissolved in a mixture of ethanol with a vegetable oil (Pharmacopoeia Martindale, 29th edition, US Pharm. XXII, 619, as well as the technical information SANDIMMUN.RTM. of the Sandoz company).
Moreover, further adjuvants other than ethanol and vegetable oil (preferably corn oil) are used to dissolve cyclosporin A and maintain it in dissolved form, such as poly(oxyethylene)-6-glycerol-tri-(oleate, linolate). The use of these adjuvants reveals the great problems involved in the administration of cyclosporin for oral administration in this form which ensures resorption at last in part.
The use of alcohol, which is always required, means a health risk for persons such as those suffering from liver diseases, alcoholics, epileptics, patients with cerebral disorders, and children. Moreover, the alcohol may reduce or increase the effects of other drugs administered simultaneously with cyclosporin.
The poly(oxyethylene)-6-glycerol-tri-oleates or linolates, which are used to achieve an improved solubility of the cyclosporins, may result in undesirable effects since they take an influence not only on cyclosporin resorption but also other substances such as fats, paraffins, vitamins, etc. Apart therefrom, the used quantities of these adjuvants should not exceed the level of 25 mg per kg of body weight. These substances may moreover induce undesirable allergic responses as intense as up to a physiological shock condition.
From a theoretical point of view it could also be possible to dissolve cyclosporin in pure vegetable oil for subsequent oral administration. In practice, however, this is not feasible because the patients are very reluctant to swallow pure oil and as resorption is not ensured.
The predominant problem involved in the aforedescribed forms of application of cyclosporin(s) for oral administration is, as a matter of fact, the poor and moreover strongly varying cyclosporin resorption. Resorption may be incomplete and varies strongly on an intra-patient basis; it may even be subject to intra-patient variations on a daily basis; in general it amounts to a level between 20 and 50% of the administered dose of cyclosporin(s). A uniform and homogeneous resorption would, however, be extremely desirable. Furthermore, it would be sensible to have cyclosporin preparations available which will globally ensure a better resorption, which means an improved biologic availability.
Even though the problems described here have been known for a long time attempts have so far been unsuccessful to find an optimum form for the oral administration of cyclosporin(s).
One object of the present invention therefore resides in the aspect to provide a pharmaceutical preparation containing cyclosporin(s), which will permit a better (increased) and more uniform resorption of cyclosporin(s) in administration per os. Intra-and inter-individual variations of cyclosporin levels in the blood are reduced.
Another object of the present invention consists in the provision of a pharmaceutical preparation for cyclosporin(s) for application, which does not contain any alcohol.
It is a further object of the present invention to dispense with additional adjuvants such as poly(oxyethylene)-40-castor oil as far as this is possible.